Cited by 2,961Protein Degradation and InhibitorsChromatin Remodeling and CancerGenomics and Chromatin Dynamics

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Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

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Lovén, Jakob, Hoke, Heather A., Lin, Charles Y., Lau, Ashley, Orlando, David A., Vakoc, Christopher R., Bradner, James E., Lee, Tong Ihn, Young, Richard A.·2013·Cell

DOI 10.1016/j.cell.2013.03.036PMC PMC3760967

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Abstract

Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.

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Authors: Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A.
Affiliations: Whitehead Institute for Biomedical Research (US)
Dana-Farber Cancer Institute (US)
Cold Spring Harbor Laboratory (US)
Harvard University (US)
Corresponding author: Young, Richard A.
ORCID: Lin, Charles Y.
Orlando, David A.
Vakoc, Christopher R.
Bradner, James E.
Lee, Tong Ihn
Young, Richard A.
Venue: Cell
Publisher: Elsevier BV
Published: 2013-04
Volume: 153
Issue: 2
Pages: 320-334
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2013.03.036
PMC: PMC3760967
OpenAlex: W1523117612
Cited by: 2,961
References: 86
Citations by year: 2026: 140 · 2025: 214 · 2024: 261 · 2023: 254 · 2022: 271 · 2021: 327 · 2020: 263 · 2019: 248 · 2018: 218 · 2017: 205 · 2016: 184 · 2015: 175 · 2014: 143 · 2013: 53
FWCI: 83.08
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders: National Institutes of Health (5p30ca045508-35)
National Human Genome Research Institute (HG002668, R01HG002668)
National Cancer Institute (CA146445, R01CA146445, P30-CA045508, CA45508, P30CA014051)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: super-enhancers, BRD4, MYC oncogene, multiple myeloma, BET inhibitors, JQ1, Mediator complex, transcriptional coactivator, transcription elongation, chromatin regulators, cancer therapy, enhancer disruption
MeSH terms: Bromodomain Containing Proteins, Antineoplastic Agents, Azepines, Chromatin, Enhancer Elements, Genetic, Humans, Multiple Myeloma, Neoplasms, Nuclear Proteins, Transcription Factors, Transcription, Genetic, Triazoles, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, Cell Line, Tumor, Genome-Wide Association Study, Mediator Complex, Transcription Elongation, Genetic

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